The medical use of chelants is now well established, for example as stabilisers for pharmaceutical preparations, as antidotes for poisonous heavy metal species, as carriers for diagnostically or therapeutically useful metal ions, for example in contrast media for use in magnetic resonance, X-ray or ultrasound imaging or in scintigraphy.
For such diagnostic agents, it is generally important that the chelate complexes should be stable both kinetically and thermodynamically and for this reason there has been much interest in the macrocyclic polyamine-based chelates, in particular DOTA and its derivatives and analogues, which form very stable complexes with the lanthanide metal ions such as gadolinium and dysprosium which are favoured diagnostic metal ions for magnetic resonance imaging due to their relatively large effects on the relaxation times (e.g. T.sub.1 and T.sub.2.sup.*) of neighbouring water protons.
The paramagnetic lanthanide metal ions useful as MR imaging contrast agents are relatively toxic and for clinical use must be administered in a form which allows little or no release of the metal for subsequent biological uptake and retention. For this reason, from the early years of MR contrast agents, the use of stable chelate complexes has been proposed. Thus the first commercial lanthanide based MR imaging contrast agent, Magnevist, contained GdDTPA, a complex with a high stability constant which following parenteral administration is excreted relatively rapidly by glomerular filtration with the gadolinium still in the chelate complex.
GdDOTA has an even higher pK.sub.HL and thus was also a prime candidate for consideration as an MR imaging contrast agent. DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) and HPDO3A (1-(2-hydroxypropyl)-4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid) have indeed been proposed as chelants for MR imaging contrast agents and GdDOTA and GdHPDO3A have been commercially developed by companies active in this field.
The lanthanide metals generally have a stable +3 oxidation state and DOTA with its four carboxylic acid groups results in a charged complex, i.e. GdDOTA.sup.-, requiring a counterion. Analogous uncharged complexes may be produced by eliminating one of DOTA's nitrogen-attached carboxymethyl groups or by replacing it by a non-ionizing group, i.e. by using a chelant such as DO3A (1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid) or HPDO3A.
Contrast media based on such non-ionic, or overall charge neutral, complexes have lower osmolalities for a given metal ion concentration and can demonstrate other improved properties relative to the analogous charged complexes. Moreover, the ring nitrogen "freed" by removal of the carboxymethyl group in moving from DOTA to DO3A can of course be substituted by groups which can act to enhance the hydrophilicity or lipophilicity or other biodistribution affecting properties of the chelate.
Recently, there has been growing interest in the use of chelants capable of chelating more than one metal ion per chelant molecule as carriers for paramagnetic or heavy metal ions for MR or X-ray imaging contrast agents. These polychelants offer several advantages over the monochelants such as DTPA, DO3A or DOTA. Thus for example, the osmolality at a given metal concentration can be reduced still further, the simultaneous delivery of a plurality of metal ions to a target site can be facilitated, and more efficient contrast agents can be produced.
Polychelants range from dichelants through oligochelants to true polychelants having perhaps hundreds of chelant moieties per molecule. Many such compounds have been described but there is still a need for polychelants, and in particular oligochelants and especially dichelants, having improved properties in terms for example of relaxivity, stability, biodistribution, biotolerability, viscosity, solubility and osmolality.
Particular macrocyclic dichelants described in the literature include the DO3A dimers of formula II, III and IV whose preparation has been described by Schering AG in EP-A-255471 and EP-A-485045 (U.S. Pat. No. 5,277,895) and elsewhere. ##STR2## (described by Schering AG in EP-A-255471 and in a poster presented at the European Congress of NMR in Medicine and Biology at Strasbourg in May 1990) ##STR3## (described by Schering AG in EP-A-255471) ##STR4## (described by Schering AG in EP-A-485045 (U.S. Pat. No. 5,277,895).
All of these macrocyclic chelant dimers have the general formula DO3A'-L-DO3A' where DO3A' is a ring nitrogen deprotonated DO3A residue and L is a linker group.
With lanthanides such as gadolinium, these macrocyclic dimers will produce non-ionic dichelates and these compounds have been found to possess high relaxivity. Thus for example the T1 relaxivities of the bisgadolinium chelates of the compounds of formula II are almost double the T1 relaxivity of GdDO3A.